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-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-08T00:08:56.813Z Has data issue: false hasContentIssue false

15 - Metabolic and neurodegenerative disorders across the lifespan

from Section II - Disorders

Published online by Cambridge University Press:  07 May 2010

By
Richard Ziegler  and
Elsa Shapiro
Edited by
Jacobus Donders  and
Scott J. Hunter
Jacobus Donders
Affiliation:
Mary Free Bed Rehabilitation Hospital
Scott J. Hunter
Affiliation:
University of Chicago
Get access

Summary

Introduction

This chapter is about the effects on the central nervous system (CNS) of inborn errors of metabolism (IEM). IEM are a large number of rare genetic disorders caused by biochemical errors. The genes that code for enzymes that convert substances (substrates) into specific products are defective. Disease is caused either by the defect/absence of a specific enzyme that disrupts a metabolic pathway causing abnormal build-up of substrate in cells or by the defect/absence of important proteins or enzymes that help in the synthesis of essential compounds.

Inborn errors of metabolism can be categorized into disorders of carbohydrate metabolism (e.g. galactosemia), amino acid metabolism (e.g. phenylketonuria and maple syrup urine disease), lysosomal storage, peroxisomal function, and a myriad of others not covered in this chapter. Although the majority of IEM have some CNS effects, this chapter will concentrate on lysosomal storage disorders and peroxisomal disorders because of the known CNS effects on neuropsychological function and development in both untreated and treated individuals and because of the advances in diagnosis and treatment with improved outcomes for these categories of diseases.

In the past 25 years, inborn errors of metabolism that affect the CNS have been the first genetic diseases to have effective treatments. The first treatments for these disorders were alterations in diet for a number of these diseases such as phenylketonuria and maple syrup urine disease, resulting in prevention of mental retardation.

Type
Chapter
Information
Principles and Practice of Lifespan Developmental Neuropsychology , pp. 427 - 448
Publisher: Cambridge University Press
Print publication year: 2010

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

Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001.
Bjoraker, K, Delaney, K, Peters, C, Krivit, W, Shapiro, E. Long term outcomes of adaptive functions for children with MPS I. J Dev Behav Pediatr 2006;27:290–6.CrossRefGoogle Scholar
Shapiro, E, Krivit, W, Lockman, L, Jambaqué, I, Peters, C, Cowan, M, et al. Long-term beneficial effect of bone marrow transplantation for childhood onset cerebral X-linked adrenoleukodystrophy. Lancet 2000;356:713–18.CrossRefGoogle ScholarPubMed
Peters, C, Charnas, L, Tan, Y, Ziegler, R, Shapiro, E, DeFor, T, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004;104:881–8.CrossRefGoogle ScholarPubMed
Peters, C, Shapiro, E, Anderson, J, Henslee-Downey, J, Klemperer, M, Cowan, M, et al. Hurler Syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. Blood 1998;91:2601–8.Google ScholarPubMed
Peters, C, Balthazor, M, Shapiro, E, King, R, Kollman, C, Hegland, J, et al. Outcome of unrelated donor bone marrow transplantation in forty children with Hurler syndrome. Blood 1996;87:4894–902.Google ScholarPubMed
Brandt, J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychol 1991;5:125–42.CrossRefGoogle Scholar
Benedict, RHB, Schretlen, D, Groninger, L, Dobraski, M, Shpritz, B. Revision of the Brief Visuospatial Memory Test: studies of normal performance, reliability, and validity. Psychol Assess 1996;8:145–53.CrossRefGoogle Scholar
Sirois, P, Posner, M, Stehbens, JA, Loveland, KA, Nichols, S, Donfield, SM, et al. Hemophilia Growth and Development Study. Quantifying practice effects in longitudinal research with the WISC-R and WAIS-R: A study of children and adolescents with hemophilia and male siblings without hemophilia. J Ped Psychol 2002;27:121–31.CrossRefGoogle ScholarPubMed
Salthouse, TA, Berish, . Correlates of within-person (across-occasion) variability in reaction time. Neuropsychology 2005;19:77–87.CrossRefGoogle ScholarPubMed
Fuentes, K, Hunter, MA, Strauss, E, Hultsch, DF. Intraindividual variability in cognitive performance in persons with chronic fatigue syndrome. Clin Neuropsychol 2001;15:210–27.CrossRefGoogle ScholarPubMed
Strauss, E, Hultsch, DF, Hunter, M, Slick, DJ, Patry, B, Levy-Bencheton, J. Using intraindividual variability to detect malingering in cognitive performance. Clin Neuropsychol 1999;13:420–32.CrossRefGoogle ScholarPubMed
Strauss, E, MacDonald, S, Hunter, M, Moll, A, Hultsch, DF. Intraindividual variability in cognitive performance in three groups of older adults: cross-domain links to physical status and self-perceived affect and beliefs. J Int Neuropsych Soc 2002;8:893–906.CrossRefGoogle ScholarPubMed
Macdonald, S, Hultsch, DF, Bunce, D.Intraindividual variability in vigilance performance: does degrading visual stimuli mimic age-related “neural noise”?’J Clin Exp Neuropsychol 2006;28:655–75.CrossRefGoogle Scholar
Russell, VA, Oades, RD, Tannock, R, Killeen, PR, Auerbach, JG, Johansen, EB, Sagvolden, T. Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis. Behav Brain Funct 2006;2:30.CrossRefGoogle ScholarPubMed
Goldman, D, Shapiro, E, Nelson, CA. Measurement of vigilance in 2-year old children. Dev Neuropsychol 2004;25:227–50.CrossRefGoogle ScholarPubMed
Jordan, C, Hughes, S, Johnson, A, Shapiro, E. The Color Object Association Test (COAT): the development of a new measure of declarative memory for 18 to 36 month-old toddlers. Child Neuropsychol 2008;14:21–41.CrossRefGoogle ScholarPubMed
Roid, Gale H. Stanford Binet Intelligence Scale, 5th edn., Rolling Meadows, IL: Riverside; 2003.Google Scholar
Wechsler, D. Wechsler Intelligence Scale for Children. Fourth Edition. San Antonio, TX: Harcourt Assessments; 2003.Google Scholar
Mullen, E. The Mullen Scales of Early Learning. Bloomington, MN: Pearson Assessments; 1995.Google Scholar
Bayley, N. Bayley Scales of Infant Development II. San Antonio, TX: Harcourt Assessments; 1993.Google Scholar
Shapiro, E, Balthazor, M. Metabolic and neurodegenerative disorders of childhood. In Taylor, G.Ris, D, Yeates, K, eds. Pediatric Neuropsychology: Research, Theory and Practice. New York: Guilford Press; 2001: 171–205.Google Scholar
Charnas, L, Ziegler, R, Shapiro, E. Pediatric chronic disease. In Rizzo, M, Eslinger, P, eds. Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA: Saunders; 2004: 983–99.Google Scholar
Martin, HR, Poe, MD, Reinhartsen, D, Pretzel, RE, Roush, J, Rosenberg, A, Dusing, SC, Escolar, M. Methods for assessing neurodevelopment in lysosomal storage diseases and related disorders: a multidisciplinary perspective. Acta Pædiatr 2008;97:69–75.CrossRefGoogle ScholarPubMed
Kempen, J, Kritchevsky, M, Feldman, ST. Effect of visual impairment on neuropsychological test performance. J Clin Exp Neuropsychol 1994;16:223–31.CrossRefGoogle ScholarPubMed
Das, JP, Ojile, E. Cognitive processing of students with and without hearing loss. J Spec Educ 1995;29:323–36.CrossRefGoogle Scholar
Krivit, W, Lockman, L, Watkins, P.A, Hirsch, J, Shapiro, E. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inher Metab Dis 1995;18:398–412.CrossRefGoogle ScholarPubMed
Ashworth, JL, Biswas, S, Wraith, E, Lloyd, IC. Mucopolysaccharidoses and the eye. Survey Ophthal 2006;51:1–17.CrossRefGoogle ScholarPubMed
Sakai, S, Hirayama, K, Ogura, K, Sakai, N, Sudoh, M, Murata, N, Iwasaki, S. Visual function of a patient with advanced adrenoleukodystrophy: comparison of luminance and color contrast sensitivities. Brain Dev 2008;30:68–72.CrossRefGoogle ScholarPubMed
Baumann, N, Turpin, J-C, Lefevre, M, Colsch, B. Motor and psycho-cognitive clinical types in adult metachromatic leukodystrophy: genotype/phenotype relationships. J Physiol Paris 2002;96:301–6.CrossRefGoogle ScholarPubMed
Shapiro, E, Lipton, M, Krivit, W. White matter dysfunction and its neuropsychological correlates: a longitudinal study of a case of metachromatic leukodystrophy treated with bone marrow transplant. J Clin Exp Neuropsychol 1992;14:610–24.CrossRefGoogle ScholarPubMed
Shapiro, E, Thrall, M, Peters, C, Krivit, W. Language, hearing loss, and mental development in Hurler syndrome. J Int Neuropsychol Soc 2000;6:161(Abstract).Google Scholar
Öz, G, Tkác, I, Charnas, L, Choi, I-Y, Bjoraker, K. Shapiro, E, Gruetter, R. Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology 2005;64:434–41.CrossRefGoogle ScholarPubMed
Schneider, JFL, Il'yansov, KA, Boltshauser, E, Henniga, J, Martin, E. Diffusion tensor imaging in cases of adrenoleukodystrophy: preliminary experience as a marker for early demyelination?Am J Neuroradiol 2003;24:819–24.Google ScholarPubMed
Nelson, J, Crowhurst, J, Carey, B, Greed, L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet 2003;123A:310–13.CrossRefGoogle ScholarPubMed
Whitley, C, Draper, KA, Dutton, CM, Brown, PA, Severson, SL, France, . Diagnostic test for mucopolysaccharidosis. II. Rapid quantification of glycosaminoglycan in urine samples collected on a paper matrix. Clin Chem 1989;35:2074–81.Google ScholarPubMed
Neufeld, EF, Muenzer, J. The mucopolysaccharidoses. In Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001: 3421–52.Google Scholar
Whitley, CB. The mucopolysaccharidoses. In Moser, HW, ed. Neurodystrophies and Neurolipidoses, vol. 22 of Handbook of Clinical Neurology. Amsterdam: Elsevier; 1996: 281–328.Google Scholar
Muenzer, J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144:S27–34.CrossRefGoogle ScholarPubMed
Sparrow, S, Cicchetti, D, Balla, D.Vineland Adaptive Behavior Scales, 2nd edn. Bloomington, MN: Pearson Assessments; 1984.Google Scholar
Bzoch, K, League, R, Brown, V.Receptive–Expressive Emergent Language Scale, 3rd edn. Austin, TX: Pro-Ed; 2003.Google Scholar
Ireton, H.Child Development Inventory (CDI). Minneapolis, MN: Behavior Science Systems; 1992.Google Scholar
Zimmerman, I, Steiner, V, Pond, R.Preschool Language Scale, 4th edn. San Antonio, TX: Harcourt Assessment; 2002.Google Scholar
Krivit, W, Sung, J, Shapiro, E, Lockman, L. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transpl 1995;4:385–92.CrossRefGoogle ScholarPubMed
Staba, SL, Escolar, ML, Poe, M, Kim, Y, Martin, PL, Szabolcs, P, et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med 2004;350:1960–9.CrossRefGoogle ScholarPubMed
Souillet, G, Guffon, N, Maire, I, Pujol, M, Taylor, P, Sevin, F, et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transpl 2003;31:1105–17.CrossRefGoogle ScholarPubMed
Tolar, J, Grewal, S, Bjoraker, K, Whitley, C, Shapiro, E, Charnas, L, Orchard, P. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transpl 2007;41:531–5.CrossRefGoogle ScholarPubMed
Wraith, JE, Beck, M, Lane, R, vander Ploeg, A, Shapiro, E, Guffon, N. Enzyme replacement therapy for mucopolysaccharidosis I patients less than 5 years old: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 2007;120: e37–46.CrossRefGoogle Scholar
Matheus, G, Castillo, M, Smith, JK, Armao, D, Towle, D, Muenzer, J.Brain MRI findings in patients with mucopolysaccharidosis types I and II and mild clinical presentation. Neuroradiology 2004;46:666–72.CrossRefGoogle ScholarPubMed
Walkley, SU.Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol 2004;15:433–44.CrossRefGoogle ScholarPubMed
Karachunski, P, Clark, B, Shapiro, E. Distribution of lysosomal storage in the CNS neurons in patients with Mucopolysaccharidosis Type I. In Proceedings of the 1st annual WORLD symposium of the Lysosomal Disease Network, Minneapolis, MN: May 2004: 33.Google Scholar
Greenberg, L. The Test of Variables of Attention (T.O.V.A.). Los Alamitos, CA: The TOVA Company; 1996.Google Scholar
Vijay, S, Wraith, JE. Clinical presentation and follow-up of patients with the attenuated phenotype of mucopolysaccharidosis type I. Acta Paediatr 2005;94:872–7.CrossRefGoogle ScholarPubMed
Elkin, TD, Megason, G, Robinson, A, Bock, H-GO, Schrimsher, G, Muenzer, J.Longitudinal neurocognitive outcome in an adolescent with Hurler-Scheie syndrome. Neuropsychiatr Dis Treat 2006;2:381–6.CrossRefGoogle Scholar
Bjoraker, K, Charnas, L, Whitley, CB, Delaney, K, Shapiro, E. Neuropsychological function in attenuated MPS I: possible decline of memory and visual spatial function. In Proceedings of the International Neuropsychological Society meetings; Boston, MA: February 2006: 144.Google Scholar
Shapiro, E, Thomas, K, Guler, E, Delaney, K, Bjoraker, K, Whitley, C, Charnas, L. Neuroimaging and neuropsychological function and neuroimaging in severe and attenuated mucopolysaccharidosis I. In Proceedings of the 4th WORLD symposium of the Lysosomal Disease Network, Mol Gen Metab XX; Las Vegas, NV: Feb 2008; 32.Google Scholar
Kakkis, E, McEntee, M, Vogler, C, Le, S, Levy, B, Belichenko, P, Passage, M. et al. Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. Mol Gen Metab 2004;83:163–74.CrossRefGoogle ScholarPubMed
Martin, R, Beck, M, Eng, C, Giugliani, R, Harmatz, P, Muñoz, V, Muenzer, J. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008;121:e377–86.CrossRefGoogle Scholar
Muenzer, J, Wraith, JE, Beck, M, Giugliani, R, Harmatz, P, Eng, C, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Gen Med 2006;8:465–73.Google Scholar
Barone, R, Nigro, F, Triulzi, F, Musumeci, S, Fiumara, A, Pavone, L. Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanfilippo syndrome). Neuropediatrics 1999;30:270–4.CrossRefGoogle Scholar
Colville, GA, Watters, JP, Yule, W, Bax, M. Sleep problems in children with Sanfilippo syndrome. Dev Med Child Neurol 1996;38:538–44.CrossRefGoogle ScholarPubMed
Potegal, M, Shapiro, E. Delineation of the MPS III behavioral phenotype. In Proceedings of the 4th annual WORLD symposium of the Lysosomal Disease Network, Mol Gen Metab XX; Las Vegas, NV: Feb 2008;11.Google Scholar
Klein, K, Krivit, W, Whitley, C, Peters, C, Cool, VA, Fuhrman, M, et al. Poor cognitive outcome of nine children with Sanfilippo Syndrome following after bone marrow transplantation and successful engraftment. Bone Marrow Transpl 1995;15:S17681.Google Scholar
Harmatz, P, Giugliani, R, Schwartz, I, Guffon, N, Teles, EL, Miranda, MC, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. MPS VI Phase 3 Study Group. J Pediatr 2006;148:533–9.CrossRefGoogle Scholar
Moser, HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997;120:1485–508.CrossRefGoogle ScholarPubMed
Moser, HW, Moser, AB, Smith, KD, Bergin, A, Borel, J, Shankroff, J. Adrenoleukodystrophy: phenotypic variability and implications. J Inherit Metab Dis 1992;15:645–64.CrossRefGoogle ScholarPubMed
Weller, M, Liedtke, W, Petersen, D, Opitz, H, Poremba, M. Very-late-onset adrenoleukodystrophy: possible precipitation of demyelination by cerebral contusion. Neurology 1992;42:367–70.CrossRefGoogle ScholarPubMed
Shapiro, E, Lockman, L, Balthazor, M, Krivit, W. Neuropsychological outcomes in several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 1995;18:413–29.CrossRefGoogle ScholarPubMed
Tolar, J, Orchard, PJ, Bjoraker, KJ, Ziegler, RS, Shapiro, EG, Charnas, L.N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy. Bone Marrow Transpl 2007;39:211–15.CrossRefGoogle ScholarPubMed
Loes, DJ, Hite, S, Moser, H, Stillman, AE, Shapiro, E, Lockman, L, el al. Adrenoleukodystrophy: a scoring method for brain MR observation. Am J Neuroradiol 1994;15:1761–6.Google Scholar
Balthazor, M, Rajanayagam, V, Shapiro, E, Loes, D, Stillman, A, Lockman, L et al. Predicting dementia in white matter disease: magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychology (Abstract). Ann Neurol 1995;40;290.Google Scholar
Rajanayagam, V, Grad, J, Krivit, W, Loes, DJ, Lockman, L, Balthazor, M, et al. Proton MR spectroscopy of childhood adrenoleukodystrophy. Am J Neuroradiol 1996;17:1013–24.Google ScholarPubMed
Schneider, JF, Il'yansov, KA, Boltshauser, E, Hennig, J, Martin, E. Diffusion tensor imaging in cases of adrenoleukodystrophy: preliminary experience as a marker for early demyelination?Am J Neuroradiol 2003;24:819–24.Google ScholarPubMed
Gieselmann, V, Zlotogora, J, Harris, A, Wenger, D, Morris, CP. Molecular genetics of metachromatic leukodystrophy. Hum Mutat 1994;4:233–43.CrossRefGoogle ScholarPubMed
Wenger, DA, Coppola, S, Liu, S-LInsights into the diagnosis and treatment of lysosomal storage diseases. Arch Neurol 2003;60:322–8.CrossRefGoogle ScholarPubMed
Shapiro, E, Lockman, , Knopman, D, Krivit, W. Characteristics of the dementia in late-onset metachromatic leukodystrophy. Neurology 1994;44;662–5.CrossRefGoogle ScholarPubMed
Hyde, TM, Ziegler, JC, Weinberger, DR. Psychiatric disturbances in metachromatic leukodystrophy. Arch Neurol 1992;49:401–6.CrossRefGoogle ScholarPubMed
Krivit, W, Shapiro, E, Kennedy, W, Lipton, M, Lockman, L, Smith, S, Summers, C, Wenger, D, Ramsey, N, Kersey, J, Yao, JK, Kaye, E. Effective treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl J Med 1992;322:28–32.CrossRefGoogle Scholar
Pridjian, G, Humbert, J, Willis, J, Shapiro, E. Presymptomatic late-infantile metachromatic leukodystrophy treated with bone marrow transplantation. J Pediatr 1994;l2J:755–8.CrossRefGoogle Scholar
Navarro, C, Fernandez, JM, Dominguez, C, Fachal, C, Alvarez, M. Late juvenile metachromatic leukodystrophy treated with bone marrow transplantation; a 4-year follow-up study. Neurology 1996;46:254–6.CrossRefGoogle ScholarPubMed
Shapiro, E, Lipton, M, Krivit, W. White matter dysfunction and its neuropsychological correlates: a longitudinal study of a case of metachromatic leukodystrophy treated with bone marrow transplant. J Clin Exp Neuropsychol 1992;14:610–24.CrossRefGoogle ScholarPubMed
Wenger, DA. Krabbe disease (globoid cell leukodystrophy). In Rosenberg, RN, Prusiner, SB, DiMauro, S, Barchi, RL, eds. The Molecular and Genetic Basis of Neurological Disease. Boston, MA: Butterworth–Heinemann; 1997: 421–31.Google Scholar
Kolodny, EH. Globoid leukodystrophy. In Moser, HW, ed. Neurodystrophies and Neurolipidoses, vol. 66 of Handbook of Clinical Neurology. Amsterdam: Elsevier; 1996: 187–210.Google Scholar
Escolar, ML, Poe, MD, Provenzale, JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 2005;352:2069–81.CrossRefGoogle ScholarPubMed
Escolar, ML, Poe, MD, Martin, HR, Kurtzberg, J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics 2006;118:e879–89.CrossRefGoogle ScholarPubMed
Krivit, W, Shapiro, EG, Peters, C, Wagner, J, Cornu, G, Kurtzberg, J, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med 1998;338:1119–26.CrossRefGoogle ScholarPubMed
Meikle, PJ, Hopwood, JJ, Clague, AE, Carey, WFPrevalence of lysosomal storage disorders. J Am Med Assoc 1999;281:249–54.CrossRefGoogle ScholarPubMed

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
×