Ganglioside Storage Diseases: On the Road to Management

  • Thomas N. Seyfried
  • Hannah E. Rockwell
  • Karie A. Heinecke
  • Douglas R. Martin
  • Miguel Sena-Esteves
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 9)


Although the biochemical and genetic basis for the GM1 and GM2 gangliosidoses has been known for decades, effective therapies for these diseases remain in early stages of development. The difficulty with many therapeutic strategies for treating the gangliosidoses comes largely from their inability to remove stored ganglioside once it accumulates in central nervous system (CNS) neurons and glia. This chapter highlights advances made using substrate reduction therapy and gene therapy in reducing CNS ganglioside storage. Information obtained from mouse and feline models provides insight on therapeutic strategies that could be effective in human clinical trials. In addition, information is presented showing how a calorie-restricted diet might facilitate therapeutic drug delivery to the CNS. The development of multiple new therapeutic approaches offers hope that longer-term management of these diseases can be achieved. It is also clear that multiple therapeutic strategies will likely be needed to provide the most complete management.


GM1 GM2 Sandhoff disease • Tay-Sachs disease Imino sugar Gene therapy Adeno-associated virus (AAV) Calorie restriction Ketogenic diet 



Bicyclic 1-deoxygalactonojirimycin


Adeno-associated virus


Ad libitum




Central nervous system


Caloric restriction










Restricted ketogenic diet












Peripheral nervous system


Sandhoff disease


Substrate reduction therapy


Tay-Sachs disease



This work was supported in part by National Institutes of Health Grants R01NS-055195 (TNS), R21NS053993 (MSE), and U01-NS064096 (TNS, DRM, MSE), the Boston College Research Expense Fund, the Scott-Ritchey Research Center, the Lysosomal Storage Disease Research Consortium, and the National Tay-Sachs and Allied Diseases Association, Inc.


  1. Andersson U, Smith D, Jeyakumar M, Butters TD, Borja MC, Dwek RA, et al. Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. Neurobiol Dis. 2004;16(3):506–15.PubMedCrossRefGoogle Scholar
  2. Arthur JR, Lee JP, Snyder EY, Seyfried TN. Therapeutic effects of stem cells and substrate reduction in juvenile Sandhoff mice. Neurochem Res. 2012;37(6):1335–43.PubMedCrossRefGoogle Scholar
  3. Arthur JR, Wilson MW, Larsen SD, Rockwell HE, Shayman JA, Seyfried TN. Ethylenedioxy-PIP2 oxalate reduces ganglioside storage in juvenile Sandhoff disease mice. Neurochem Res. 2013;38(4):866–75. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t.PubMedCrossRefGoogle Scholar
  4. Badie B, Schartner JM, Hagar AR, Prabakaran S, Peebles TR, Bartley B, et al. Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res. 2003;9(2):872–7.PubMedGoogle Scholar
  5. Baek RC, Kasperzyk JL, Platt FM, Seyfried TN. N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. J Neurochem. 2004;90 Suppl 1:89.Google Scholar
  6. Baek RC, Kasperzyk JL, Platt FM, Seyfried TN. N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. Neurochem Int. 2008;52(6):1125–33.PubMedCrossRefGoogle Scholar
  7. Baek RC, Martin DR, Cox NR, Seyfried TN. Comparative analysis of brain lipids in mice, cats, and humans with Sandhoff disease. Lipids. 2009;44(3):197–205.PubMedCentralPubMedCrossRefGoogle Scholar
  8. Baek RC, Broekman ML, Leroy SG, Tierney LA, Sandberg MA, d’Azzo A, et al. AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS One. 2010;5(10):e13468. Research Support, N.I.H., Extramural.PubMedCentralPubMedCrossRefGoogle Scholar
  9. Baker Jr HJ, Lindsey JR, McKhann GM, Farrell DF. Neuronal GM1 gangliosidosis in a Siamese cat with beta-galactosidase deficiency. Science. 1971;174(4011):838–9. New York, NY.PubMedCrossRefGoogle Scholar
  10. Bradbury AM, Cochran JN, McCurdy VJ, Johnson AK, Brunson BL, Gray-Edwards H, et al. Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy. Mol Ther. 2013;21(7):1306–15.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Brigande JV, Platt FM, Seyfried TN. Inhibition of glycosphingolipid biosynthesis does not impair growth or morphogenesis of the postimplantation mouse embryo. J Neurochem. 1998;70:871–82.PubMedCrossRefGoogle Scholar
  12. Broekman ML, Baek RC, Comer LA, Fernandez JL, Seyfried TN, Sena-Esteves M. Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by Neonatal Adeno-associated virus-mediated gene delivery. Mol Ther. 2007;15(1):30–7.PubMedCrossRefGoogle Scholar
  13. Butters TD, Dwek RA, Platt FM. Therapeutic applications of imino sugars in lysosomal storage disorders. Curr Top Med Chem. 2003;3(5):561–74.PubMedCrossRefGoogle Scholar
  14. Cachon-Gonzalez MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox TM. Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc Natl Acad Sci U S A. 2006;103(27):10373–8.PubMedCentralPubMedCrossRefGoogle Scholar
  15. Cachon-Gonzalez MB, Wang SZ, McNair R, Bradley J, Lunn D, Ziegler R, et al. Gene transfer corrects acute GM2 gangliosidosis–potential therapeutic contribution of perivascular enzyme flow. Mol Ther. 2012;20(8):1489–500. Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  16. Chavany C, Jendoubi M. Biology and potential strategies for the treatment of GM2 gangliosidoses. Mol Med Today. 1998;4(4):158–65.PubMedCrossRefGoogle Scholar
  17. Chen JZ, Gokden N, Greene GF, Green B, Kadlubar FF. Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis. Carcinogenesis. 2003;24(9):1481–7.PubMedCrossRefGoogle Scholar
  18. Cork LC, Munnell JF, Lorenz MD, Murphy JV, Baker HJ, Rattazzi MC. GM2 ganglioside lysosomal storage disease in cats with beta-hexosaminidase deficiency. Science. 1977;196(4293):1014–7. New York, NY.PubMedCrossRefGoogle Scholar
  19. Denny CA, Kasperzyk JL, Gorham KN, Bronson RT, Seyfried TN. Influence of caloric restriction on motor behavior, longevity, and brain lipid composition in Sandhoff disease mice. J Neurosci Res. 2006;83(6):1028–38.PubMedCrossRefGoogle Scholar
  20. Denny CA, Alroy J, Pawlyk BS, Sandberg MA, d’Azzo A, Seyfried TN. Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice. J Neurochem. 2007;101(5):1294–302.PubMedCrossRefGoogle Scholar
  21. Denny CA, Heinecke KA, Kim YP, Baek RC, Loh KS, Butters TD, et al. Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. J Neurochem. 2010;113(6):1525–35.PubMedGoogle Scholar
  22. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A. 2003;100(5):2911–6.PubMedCentralPubMedCrossRefGoogle Scholar
  23. Ebato H, Seyfried TN, Yu RK. Biochemical study of heterosis for brain myelin content in mice. J Neurochem. 1983;40(2):440–6.PubMedCrossRefGoogle Scholar
  24. Ellinwood NM, Vite CH, Haskins ME. Gene therapy for lysosomal storage diseases: the lessons and promise of animal models. J Gene Med. 2004;6(5):481–506.PubMedCrossRefGoogle Scholar
  25. Fischer PB, Collin M, Karlsson GB, James W, Butters TD, Davis SJ, et al. The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding. J Virol. 1995;69(9):5791–7.PubMedCentralPubMedGoogle Scholar
  26. Folkerth RD, Alroy J, Bhan I, Kaye EM. Infantile G(M1) gangliosidosis: complete morphology and histochemistry of two autopsy cases, with particular reference to delayed central nervous system myelination. Pediatr Dev Pathol. 2000;3(1):73–86.PubMedCrossRefGoogle Scholar
  27. Freeman JM, Kossoff EH. Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv Pediatr. 2010;57(1):315–29.PubMedCrossRefGoogle Scholar
  28. Giraudo CG, Maccioni HJ. Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J Biol Chem. 2003;278(41):40262–71.PubMedCrossRefGoogle Scholar
  29. Gravel RA, Clarke JTR, Kaback MM, Mahuran D, Sandhoff K, Suzuki K. The GM2 gangliosidoses. In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill, Inc; 1995. p. 2839–79.Google Scholar
  30. Greene AE, Todorova MT, McGowan R, Seyfried TN. Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia. 2001;42(11):1371–8.PubMedCrossRefGoogle Scholar
  31. Greene AE, Todorova MT, Seyfried TN. Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J Neurochem. 2003;86(3):529–37.PubMedCrossRefGoogle Scholar
  32. Hahn CN, del Pilar MM, Schroder M, Vanier MT, Hara Y, Suzuki K, et al. Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase. Hum Mol Genet. 1997;6(2):205–11.PubMedCrossRefGoogle Scholar
  33. Hauser EC, Kasperzyk JL, d’Azzo A, Seyfried TN. Inheritance of lysosomal acid beta-galactosidase activity and gangliosides in crosses of DBA/2J and knockout mice. Biochem Genet. 2004;42(7–8):241–57.PubMedCrossRefGoogle Scholar
  34. Hayase T, Shimizu J, Goto T, Nozaki Y, Mori M, Takahashi N, et al. Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay-Sachs disease. Brain Dev. 2010;32(3):244–7. Case Reports.PubMedCrossRefGoogle Scholar
  35. Jeyakumar M, Butters TD, Cortina-Borja M, Hunnam V, Proia RL, Perry VH, et al. Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci U S A. 1999;96(11):6388–93.PubMedCentralPubMedCrossRefGoogle Scholar
  36. Jeyakumar M, Smith D, Eliott-Smith E, Cortina-Borja M, Reinkensmeier G, Butters TD, et al. An inducible mouse model of late onset Tay-Sachs disease. Neurobiol Dis. 2002;10(3):201–10.PubMedCrossRefGoogle Scholar
  37. Jeyakumar M, Thomas R, Elliot-Smith E, Smith DA, van der Spoel AC, d’Azzo A, et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain. 2003;126(Pt 4):974–87.PubMedCrossRefGoogle Scholar
  38. Kasperzyk JL, El-Abbadi MM, Hauser EC, D’Azzo A, Platt FM, Seyfried TN. N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J Neurochem. 2004;89(3):645–53.PubMedCrossRefGoogle Scholar
  39. Kasperzyk JL, d’Azzo A, Platt FM, Alroy J, Seyfried TN. Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice. J Lipid Res. 2005;46(4):744–51.PubMedCrossRefGoogle Scholar
  40. Kaye EM, Alroy J, Raghavan SS, Schwarting GA, Adelman LS, Runge V, et al. Dysmyelinogenesis in animal model of GM1 gangliosidosis. Pediatr Neurol. 1992;8(4):255–61.PubMedCrossRefGoogle Scholar
  41. Klima H, Tanaka A, Schnabel D, Nakano T, Schroder M, Suzuki K, et al. Characterization of full-length cDNAs and the gene coding for the human GM2 activator protein. FEBS Lett. 1991;289(2):260–4. Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.PubMedCrossRefGoogle Scholar
  42. Kolodny EH, Neudorfer O, Gianutsos J, Zaroff C, Barnett N, Zeng B, et al. Late-onset Tay-Sachs disease: Natural history and treatment with OGT 918. J Neurochem 2004 (Suppl.) (in press).Google Scholar
  43. Kossoff EH, Hartman AL. Ketogenic diets: new advances for metabolism-based therapies. Curr Opin Neurol. 2012;25(2):173–8.PubMedCentralPubMedCrossRefGoogle Scholar
  44. Kroll RA, Pagel MA, Roman-Goldstein S, Barkovich AJ, D’Agostino AN, Neuwelt EA. White matter changes associated with feline GM2 gangliosidosis (Sandhoff disease): correlation of MR findings with pathologic and ultrastructural abnormalities. AJNR Am J Neuroradiol. 1995;16(6):1219–26.PubMedGoogle Scholar
  45. Kyrkanides S, Miller JH, Brouxhon SM, Olschowka JA, Federoff HJ. Beta-hexosaminidase lentiviral vectors: transfer into the CNS via systemic administration. Brain Res Mol Brain Res. 2005;133(2):286–98.PubMedCrossRefGoogle Scholar
  46. Kyrkanides S, Yang M, Tallents RH, Miller JN, Brouxhon SM, Olschowka JA. The trigeminal retrograde transfer pathway in the treatment of neurodegeneration. J Neuroimmunol. 2009;209(1–2):139–42. Research Support, N.I.H., Extramural.PubMedCrossRefGoogle Scholar
  47. Lachmann RH. Miglustat. Oxford glycosciences/actelion. Curr Opin Investig Drugs. 2003;4(4):472–9.PubMedGoogle Scholar
  48. Lacorazza HD, Flax JD, Snyder EY, Jendoubi M. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med. 1996;2(4):424–9.PubMedCrossRefGoogle Scholar
  49. Larsen SD, Wilson MW, Abe A, Shu L, George CH, Kirchhoff P, et al. Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain. J Lipid Res. 2012;53(2):282–91.PubMedCentralPubMedCrossRefGoogle Scholar
  50. Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007;13(4):439–47.PubMedCrossRefGoogle Scholar
  51. Lee MC, El-Abbadi M, Orosz CG, Yates AJ, Seyfried TN. A spontaneous metastatic brain tumor in the VM mouse: histological characteristics and ganglioside composition. 1998 (submitted).Google Scholar
  52. Li SC, Nakamura T, Ogamo A, Li YT. Evidence for the presence of two separate protein activators for the enzymic hydrolysis of GM1 and GM2 gangliosides. J Biol Chem. 1979;254(21):10592–5. Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.PubMedGoogle Scholar
  53. Martin DR, Krum BK, Varadarajan GS, Hathcock TL, Smith BF, Baker HJ. An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Exp Neurol. 2004;187(1):30–7. Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.PubMedCrossRefGoogle Scholar
  54. Martin DR, Rigat BA, Foureman P, Varadarajan GS, Hwang M, Krum BK, et al. Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis. Mol Genet Metab. 2008;94(2):212–21. Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  55. McNally MA, Baek RC, Avila RL, Seyfried TN, Strichartz GR, Kirschner DA. Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis. J Negat Results Biomed. 2007;6:8. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  56. Migita M, Medin JA, Pawliuk R, Jacobson S, Nagle JW, Anderson S, et al. Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors. Proc Natl Acad Sci U S A. 1995;92(26):12075–9.PubMedCentralPubMedCrossRefGoogle Scholar
  57. Moyses C. Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci. 2003;358(1433):955–60.PubMedCentralPubMedCrossRefGoogle Scholar
  58. Mulrooney TJ, Marsh J, Urits I, Seyfried TN, Mukherjee P. Influence of caloric restriction on constitutive expression of NF-kappaB in an experimental mouse astrocytoma. PLoS One. 2011;6(3):e18085.PubMedCentralPubMedCrossRefGoogle Scholar
  59. Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL. Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet. 2002;11(11):1343–50.PubMedCrossRefGoogle Scholar
  60. Neises GR, Woodman PG, Butters TD, Ornberg RL, Platt FM. Ultrastructural changes in the Golgi apparatus and secretory granules of HL-60 cells treated with the imino sugar N-butyldeoxynojirimycin. Biol Cell. 1997;89(2):123–31.PubMedCrossRefGoogle Scholar
  61. Norflus F, Tifft CJ, McDonald MP, Goldstein G, Crawley JN, Hoffmann A, et al. Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. J Clin Invest. 1998;101(9):1881–8.PubMedCentralPubMedCrossRefGoogle Scholar
  62. O’Brien JS. b-Galactosidase deficiency (GM1 gangliosidosis, galactosialidosis, and Morquio syndrome type B); ganglioside sialidase deficiency (Mucolipidosis IV). In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill Inc.; 1989. p. 1797–806.Google Scholar
  63. Paller AS, Arnsmeier SL, Chen JD, Woodley DT. Ganglioside GT1b inhibits keratinocyte adhesion and migration on a fibronectin matrix. J Invest Dermatol. 1995;105(2):237–42.PubMedCrossRefGoogle Scholar
  64. Platt FM, Walkley SU. Lysosomal disorders of the brain. New York: Oxford University Press; 2004.CrossRefGoogle Scholar
  65. Proia RL. Glycosphingolipid functions: insights from engineered mouse models. Philos Trans R Soc Lond B Biol Sci. 2003;358(1433):879–83.PubMedCentralPubMedCrossRefGoogle Scholar
  66. Radin NS. Inhibitors and stimulators of glucocerebroside metabolism. Prog Clin Biol Res. 1982;95:357–83.PubMedGoogle Scholar
  67. Rigat BA, Tropak MB, Buttner J, Crushell E, Benedict D, Callahan JW, et al. Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy. Mol Genet Metab. 2012;107(1–2):203–12. Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  68. Sandhoff K, Harzer K. Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci. 2013;33(25):10195–208. Research Support, Non-U.S. Gov’t.PubMedCrossRefGoogle Scholar
  69. Sango K, Johnson ON, Kozak CA, Proia RL. Beta-1,4-N-Acetylgalactosaminyltransferase involved in ganglioside synthesis: cDNA sequence, expression, and chromosome mapping of the mouse gene. Genomics. 1995;27(2):362–5.PubMedCrossRefGoogle Scholar
  70. Sango K, McDonald MP, Crawley JN, Mack ML, Tifft CJ, Skop E, et al. Mice lacking both subunits of lysosomal b-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nat Genet. 1996;14:348–52.PubMedCrossRefGoogle Scholar
  71. Sano R, Annunziata I, Patterson A, Moshiach S, Gomero E, Opferman J, et al. GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol Cell. 2009;36(3):500–11. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  72. Schnaar RL. Glycolipid-mediated cell-cell recognition in inflammation and nerve regeneration. Arch Biochem Biophys. 2004;426(2):163–72.PubMedCrossRefGoogle Scholar
  73. Sekine M, Ariga T, Miyatake T, Kase R, Suzuki H, Yamakawa T. Gangliosides and neutral glycolipids in guinea pig adrenal glands. J Biochem. 1984;96:237–44.PubMedGoogle Scholar
  74. Seyfried TN. Ganglioside abnormalities associated with failed neural differentiation in a T-locus mutant mouse embryo. Dev Biol. 1987;123(1):286–91.PubMedCrossRefGoogle Scholar
  75. Takai T, Higaki K, Aguilar-Moncayo M, Mena-Barragan T, Hirano Y, Yura K, et al. A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis. Mol Ther. 2013;21(3):526–32. Research Support, Non-U.S. Gov’t.PubMedCentralPubMedCrossRefGoogle Scholar
  76. Van Der Voorn JP, Kamphorst W, Van Der Knaap MS, Powers JM. The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction. Acta Neuropathol (Berl). 2004;107(6):539–45.CrossRefGoogle Scholar
  77. Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology. 1993;3(2):97–130.PubMedCrossRefGoogle Scholar
  78. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70(3):309–19.PubMedCrossRefGoogle Scholar
  79. von Specht BU, Geiger B, Arnon R, Passwell J, Keren G, Goldman B, et al. Enzyme replacement in Tay-Sachs disease. Neurology. 1979;29:848–54.CrossRefGoogle Scholar
  80. Vunnam RR, Radin NS. Analogs of ceramide that inhibit glucocerebroside synthetase in mouse brain. Chem Phys Lipids. 1980;26(3):265–78.PubMedCrossRefGoogle Scholar
  81. Weindruch R, Kemnitz JW, Uno H. Interspecies variations in physiologic and antipathologic outcomes of dietary restriction (1988).Google Scholar
  82. Yu RK. Development regulation of ganglioside metabolism. Prog Brain Res. 1993;101:31–44.CrossRefGoogle Scholar
  83. Yu RK, Tsai YT, Ariga T, Yanagisawa M. Structures, biosynthesis, and functions of gangliosides-an overview. J Oleo Sci. 2011;60(10):537–44. Research Support, N.I.H., Extramural.PubMedCentralPubMedCrossRefGoogle Scholar
  84. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007;4:5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Thomas N. Seyfried
    • 1
  • Hannah E. Rockwell
    • 1
  • Karie A. Heinecke
    • 1
  • Douglas R. Martin
    • 2
  • Miguel Sena-Esteves
    • 3
  1. 1.Biology DepartmentBoston CollegeChestnut HillUSA
  2. 2.Scott-Ritchey Research Center and Department of Anatomy, Physiology & PharmacologyAuburn University College of Veterinary MedicineAuburnUSA
  3. 3.Department of Neurology and Gene Therapy CenterUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations