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Cholesterol Use in Autism Treatment

Abstract

Cholesterol is essential for embryological development, cellular membrane structure and function, and synthesis of hormones, bile acids, vitamin D and neuroactive steroids. Nearly one quarter of the body’s cholesterol is in the brain, reflecting its pivotal role in this organ. Altered cholesterol homeostasis has been reported in several neurologic disorders including Alzheimer’s disease, Huntington disease, Niemann Pick Disease Type C, Tangier Disease, and Smith-Lemli-Opitz Syndrome (SLOS). The latter is a disorder of the cholesterol biosynthesis pathway that results in multiple malformations, intellectual disability, and oftentimes autistic spectrum disorders (ASD). The high prevalence of ASD in individuals with SLOS suggests an overlap in the pathophysiologic mechanisms that underlie SLOS and ASD. Thus, SLOS has served as a disease model to understand the role of cholesterol in neurologic structure and function, including morphogenesis, myelination, cellular membrane stability, lipid rafts, neuroactive steroid synthesis, and signal transduction. The assessment and treatment of SLOS and its potential extension to clinical management of idiopathic ASD are discussed.

Keywords

Autistic Spectrum Disorder Autistic Spectrum Disorder Celiac Disease Lipid Raft Intellectual Disability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. AGA. AGA institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology. 2006;131(6):1977–80.CrossRefGoogle Scholar
  2. Allen IV, McQuaid S, et al. Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci. 2001;22(2):141–4.PubMedCrossRefGoogle Scholar
  3. Allen JA, Halverson-Tamboli RA, et al. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 2007;8(2):128–40.PubMedCrossRefGoogle Scholar
  4. Aneja A, Tierney E. Autism: the role of cholesterol in treatment. Int Rev Psychiatry. 2008;20(2):165–70.PubMedCrossRefGoogle Scholar
  5. Benarroch EE. Brain cholesterol metabolism and neurologic disease. Neurology. 2008;71(17):1368–73.PubMedCrossRefGoogle Scholar
  6. Ben-David E, Shifman S. Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet. 2012;8(3):e1002556.PubMedCrossRefGoogle Scholar
  7. Berg BO. Principles of child neurology. New York: McGraw-Hill Professional; 1996.Google Scholar
  8. Bjorkhem I, Lutjohann D, et al. Cholesterol homeostasis in human brain: turnover of 24S- hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation [in process citation]. J Lipid Res. 1998;39(8):1594–600.PubMedGoogle Scholar
  9. Block RC, Dorsey ER, et al. Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol. 2010;4(1):17–23.PubMedCrossRefGoogle Scholar
  10. Boyles JK, Pitas RE, et al. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest. 1985;76(4):1501–13.PubMedCrossRefGoogle Scholar
  11. Brambilla P, Hardan A, et al. Brain anatomy and development in autism: review of structural MRI studies. Brain Res Bull. 2003;61(6):557–69.PubMedCrossRefGoogle Scholar
  12. Bukelis I, Porter FD, et al. Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am J Psychiatry. 2007;164(11):1655–61.PubMedCrossRefGoogle Scholar
  13. Buonuomo PS, Ruggiero A, et al. Familial hypobetalipoproteinemia: early neurological, hematological, and ocular manifestations in two affected twins responding to vitamin supplementation. Curr Opin Pediatr. 2009;21(6):824–7.PubMedCrossRefGoogle Scholar
  14. Burwick RM, Ramsay PP, et al. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers. Neurology. 2006;66(9):1373–83.PubMedCrossRefGoogle Scholar
  15. Butchbach ME, Guo H, et al. Methyl-beta-cyclodextrin but not retinoic acid reduces EAAT3-mediated glutamate uptake and increases GTRAP3-18 expression. J Neurochem. 2003;84(4):891–4.PubMedCrossRefGoogle Scholar
  16. Caramona MM, Cotrim MD, et al. Influence of experimental hypercholesterolemia on the monoamine oxidase activity in rabbit arteries. Pharmacol Res. 1996;33(4–5):245–9.PubMedCrossRefGoogle Scholar
  17. Caruso PA, Poussaint TY, et al. MRI and (1)H MRS findings in Smith-Lemli-Opitz syndrome. Neuroradiology. 2003;5:5.Google Scholar
  18. Chu LW, Li Y, et al. A novel intronic polymorphism of ABCA1 gene reveals risk for sporadic Alzheimer’s disease in Chinese. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(8):1007–13.PubMedCrossRefGoogle Scholar
  19. Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res Rev. 2004;10(2):112–16.PubMedCrossRefGoogle Scholar
  20. Correa-Cerro LS, Porter FD. 3beta-Hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005;84(2):112–26.PubMedCrossRefGoogle Scholar
  21. Cruz ML, Wong WW, et al. Effects of infant nutrition on cholesterol synthesis rates. Pediatr Res. 1994;35(2):135–40.PubMedCrossRefGoogle Scholar
  22. Davies JE, Miller RH. Local sonic hedgehog signaling regulates oligodendrocyte precursor appearance in multiple ventricular zone domains in the chick metencephalon. Dev Biol. 2001;233(2):513–25.PubMedCrossRefGoogle Scholar
  23. Dehouck B, Fenart L, et al. A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier. J Cell Biol. 1997;138(4):877–89.PubMedCrossRefGoogle Scholar
  24. Dodelet-Devillers A, Cayrol R, et al. Functions of lipid raft membrane microdomains at the blood–brain barrier. J Mol Med (Berl). 2009;87(8):765–74.CrossRefGoogle Scholar
  25. Dziobek I, Gold SM, et al. Hypercholesterolemia in Asperger syndrome: independence from lifestyle, obsessive-compulsive behavior, and social anxiety. Psychiatry Res. 2007;149(1–3):321–4.PubMedCrossRefGoogle Scholar
  26. Elias ER, Irons MB, et al. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet. 1997;68(3):305–10.PubMedCrossRefGoogle Scholar
  27. Elmehdawi R. Hypolipidemia: a word of caution. Libyan J Med. 2008;3(2):84–90.PubMedCrossRefGoogle Scholar
  28. Ettinger W. Causes of hypocholesterolemia. Coronary Artery Disease. 1993;4(10):854–9.PubMedCrossRefGoogle Scholar
  29. Fitzky BU, Witsch-Baumgartner M, et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 1998;95(14):8181–6.PubMedCrossRefGoogle Scholar
  30. Gimpl G, Burger K, et al. Cholesterol as modulator of receptor function. Biochemistry. 1997;36(36):10959–74.PubMedCrossRefGoogle Scholar
  31. Green L, Fein D, et al. Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry. 2001;50(8):609–13.PubMedCrossRefGoogle Scholar
  32. Hardan AY, Pabalan M, et al. Corpus callosum volume in children with autism. Psychiatry Res. 2009;174(1):57–61.PubMedCrossRefGoogle Scholar
  33. Hardy SC, Kleinman RE. Fat and cholesterol in the diet of infants and young children: implications for growth, development, and long-term health. J Pediatr. 1994;125(5 Pt 2):S69–77.PubMedCrossRefGoogle Scholar
  34. Hollander E, Bartz J, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61(4):498–503.PubMedCrossRefGoogle Scholar
  35. Hu VW, Nguyen A, et al. Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis. PLoS One. 2009;4(6):e5775.PubMedCrossRefGoogle Scholar
  36. Huang X, Chen P, et al. Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol. 2006;63(2):189–93.PubMedCrossRefGoogle Scholar
  37. Irons M, Elias ER, et al. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome [letter]. Lancet. 1993;341(8857):1414.PubMedCrossRefGoogle Scholar
  38. Irons M, Elias ER, et al. Clinical features of the Smith-Lemli-Opitz syndrome and treatment of the cholesterol metabolic defect. International Pediatrics. 1995;10(1):28–32.Google Scholar
  39. Janusonis S. Origin of the blood hyperserotonemia of autism. Theor Biol Med Model. 2008;5:10.PubMedCrossRefGoogle Scholar
  40. Jones PJ. Regulation of cholesterol biosynthesis by diet in humans. Am J Clin Nutr. 1997;66(2):438–46.PubMedGoogle Scholar
  41. Joseph DB, Uehling DT, et al. Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome. J Urol. 1987;137(4):719–21.PubMedGoogle Scholar
  42. Kaplan RN, Bussel JB. Differential diagnosis and management of thrombocytopenia in childhood. Pediatr Clin North Am. 2004;51(4):1109–40. xi.PubMedCrossRefGoogle Scholar
  43. Karasinska JM, Hayden MR. Cholesterol metabolism in Huntington disease. Nat Rev Neurol. 2011;7(10):561–72.PubMedCrossRefGoogle Scholar
  44. Kelley RI. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin Chim Acta. 1995;236(1):45–58.PubMedCrossRefGoogle Scholar
  45. Kelley R. A new face for an old syndrome. Am J Med Genet. 1997;68:251–6.PubMedCrossRefGoogle Scholar
  46. Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000;37(5):321–35.PubMedCrossRefGoogle Scholar
  47. Kelley RI, Herman GE. Inborn errors of sterol biosynthesis. Annu Rev Genomics Hum Genet. 2001;2:299–341.PubMedCrossRefGoogle Scholar
  48. Kelley RL, Roessler E, et al. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of sonic hedgehog? Am J Med Genet. 1996;66(4):478–84.PubMedCrossRefGoogle Scholar
  49. Kim EK, Neggers YH, et al. Alterations in lipid profile of autistic boys: a case control study. Nutr Res. 2010;30(4):255–60.PubMedCrossRefGoogle Scholar
  50. Lee R W Y T, E. Hypothesis: the role of serols in autism spectrum disorder. Autism Res Treat 2011;7:2.Google Scholar
  51. Linetti A, Fratangeli A, et al. Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci. 2010;123(Pt 4):595–605.Google Scholar
  52. Marion RW, Alvarez LA, et al. Computed tomography of the brain in the Smith-Lemli-Opitz syndrome. J Child Neurol. 1987;2(3):198–200.PubMedCrossRefGoogle Scholar
  53. Martens JR, O’Connell K, et al. Targeting of ion channels to membrane microdomains: localization of KV channels to lipid rafts. Trends Pharmacol Sci. 2004;25(1):16–21.PubMedCrossRefGoogle Scholar
  54. Martin-Ruiz CM, Lee M, et al. Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res. 2004;123(1–2):81–90.PubMedCrossRefGoogle Scholar
  55. Matsuzaki H, Iwata K, Suda S, Tsuchiya KY, Suzuki K, Nakamura K, Tsujii M, Takei N. Dyslipidemia in male patients with high-functioning autism. Poster presentation international meeting for autism research. Philadelphia; 2010. https://imfar.confex.com/imfar/2010/webprogram/Paper5320.html.
  56. Meyer-Lindenberg A, Domes G, et al. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci. 2011;12(9):524–38.PubMedCrossRefGoogle Scholar
  57. National Heart, Lung, and Blood Institute. U.S. Department of Health and Human Services. NIH Publication No. 12-7486, October 2012.Google Scholar
  58. NHANES. NHANES: National Health and Nutrition Examination Survey III. 2008. From http://www.cdc.gov/nchs/about/major/nhanes/datatblelink.htm. Accessed 26 Aug 2008.
  59. Nishimori K, Takayanagi Y, et al. New aspects of oxytocin receptor function revealed by knockout mice: sociosexual behaviour and control of energy balance. Prog Brain Res. 2008;170:79–90.PubMedCrossRefGoogle Scholar
  60. Nwokoro NA, Mulvihill JJ. Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome. Am J Med Genet. 1997;68(3):315–21.PubMedCrossRefGoogle Scholar
  61. Pfrieger FW. Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci. 2003;60(6):1158–71.PubMedGoogle Scholar
  62. Quest AF, Leyton L, et al. Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease. Biochem Cell Biol. 2004;82(1):129–44.PubMedCrossRefGoogle Scholar
  63. Rakheja D, Boriack RL. Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata. Pediatr Dev Pathol. 2008;11(2):128–32.PubMedCrossRefGoogle Scholar
  64. Reversi A, Rimoldi V, et al. Effects of cholesterol manipulation on the signaling of the human oxytocin receptor. Am J Physiol Regul Integr Comp Physiol. 2006;291(4):R861–9.PubMedCrossRefGoogle Scholar
  65. Ribes V, Briscoe J. Establishing and interpreting graded sonic hedgehog signaling during vertebrate neural tube patterning: the role of negative feedback. Cold Spring Harb Perspect Biol. 2009;1(2):a002014.PubMedCrossRefGoogle Scholar
  66. Saher G, Brugger B, et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 2005;8(4):468–75.PubMedGoogle Scholar
  67. Salvati S, Attorri L, et al. Diet, lipids and brain development. Dev Neurosci. 2000;22(5–6):481–7.PubMedCrossRefGoogle Scholar
  68. Scanlon SM, Williams DC, et al. Membrane cholesterol modulates serotonin transporter activity. Biochemistry. 2001;40(35):10507–13.PubMedCrossRefGoogle Scholar
  69. Schengrund CL, Ali-Rahmani F, et al. Cholesterol, GM1, and autism. Neurochem Res. 2012;37(6):1201–7.PubMedCrossRefGoogle Scholar
  70. Services, U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th Edition, Washington, DC: U.S. Government Printing Office; 2010.Google Scholar
  71. Sikora DM, Ruggiero M, et al. Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J Pediatr. 2004;144(6):783–91.PubMedGoogle Scholar
  72. Sikora DM, Pettit-Kekel K, et al. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2006;140(14):1511–18.PubMedCrossRefGoogle Scholar
  73. Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997;387(6633):569–72.PubMedCrossRefGoogle Scholar
  74. Smith DW, Lemli L, et al. A newly recognized syndrome of multiple congenital anomalies. J Pediatr. 1964;64:210–17.PubMedCrossRefGoogle Scholar
  75. Sooksawate T, Simmonds MA. Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones. Neuropharmacology. 2001;40(2):178–84.PubMedCrossRefGoogle Scholar
  76. Strous RD, Golubchik P, et al. Lowered DHEA-S plasma levels in adult individuals with autistic disorder. Eur Neuropsychopharmacol. 2005;15(3):305–9.PubMedCrossRefGoogle Scholar
  77. Takemoto-Kimura S, Ageta-Ishihara N, et al. Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIgamma. Neuron. 2007;54(5):755–70.PubMedCrossRefGoogle Scholar
  78. Tassoni D, Kaur G, et al. The role of eicosanoids in the brain. Asia Pac J Clin Nutr. 2008;17 Suppl 1:220–8.PubMedGoogle Scholar
  79. Tierney E, Nwokoro NA, et al. Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome. Ment Retard Dev Disabil Res Rev. 2000;6(2):131–4.PubMedCrossRefGoogle Scholar
  80. Tierney E, Nwokoro NA, et al. Behavior phenotype in the RSH/smith-Lemli-Opitz syndrome. Am J Med Genet. 2001;98(2):191–200.PubMedCrossRefGoogle Scholar
  81. Tierney E, Bukelis I, et al. Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(6):666–8.PubMedCrossRefGoogle Scholar
  82. Ullrich K, Koch HG, et al. Smith-Lemli-Opitz syndrome: treatment with cholesterol and bile acids. Neuropediatrics. 1996;27(2):111–12.PubMedCrossRefGoogle Scholar
  83. Vance DE, Van den Bosch H. Cholesterol in the year 2000. Biochim Biophys Acta. 2000;1529(1–3):1–8.PubMedGoogle Scholar
  84. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454–72.PubMedCrossRefGoogle Scholar
  85. Waage-Baudet H, Lauder JM, et al. Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism. Int J Dev Neurosci. 2003;21(8):451–9.PubMedCrossRefGoogle Scholar
  86. Waage-Baudet H, Dunty Jr WC, et al. Immunohistochemical and microarray analyses of a mouse model for the smith-Lemli-Opitz syndrome. Dev Neurosci. 2005;27(6):378–96.PubMedCrossRefGoogle Scholar
  87. Williams VJ, Leritz EC, et al. Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Hum Brain Mapp. 2012; 16. [Epub ahead of print].Google Scholar
  88. Wilson L, Maden M. The mechanisms of dorsoventral patterning in the vertebrate neural tube. Dev Biol. 2005;282(1):1–13.PubMedCrossRefGoogle Scholar
  89. Zeng X, Goetz JA, et al. A freely diffusible form of sonic hedgehog mediates long-range signalling. Nature. 2001;411(6838):716–20.PubMedCrossRefGoogle Scholar
  90. Zhang J, Muldoon MF, et al. Association of serum cholesterol and history of school suspension among school-age children and adolescents in the United States. Am J Epidemiol. 2005;161(7):691–9.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of PsychiatryKennedy Krieger InstituteBaltimoreUSA

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