Urinary p-Cresol in ASD

Abstract

The etiology of autism encompasses a broad range of causative events, ranging from rare de novo high-penetrance mutations affecting genes such as NLGN3/4, SHANK3, NRXN1, and MECP2 to a complex mix of environmental and epigenetic factors acting upon a vulnerable genetic background. Increasing prevalence rates, decreasing heritability estimates, and polygenic models with multiple incompletely penetrant de novo mutations all suggest that in addition to broader diagnostic criteria and increased awareness, a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Notably, the phenotypic heterogeneity of ASD suggests the existence of many “autisms,” each characterized by specific etiopathogenetic underpinnings. Given the complex nature of this disorder, great effort is now under way aiming to define a reliable panel of biological markers able to assist clinicians in an early diagnosis. p-Cresol (4-methylphenol) belongs to the cresol class of organic aromatic compounds. Environmental p-cresol is absorbed through the gastrointestinal and the respiratory tracts, as well as through the intact skin. Physiological sources of p-cresol are represented by some gut bacteria which express synthetic enzymes not found in human cells. Urinary p-cresol or its conjugated derivative p-cresylsulfate holds the promise of representing one of these biomarkers in small autistic children and could contribute to identify a subgroup of ASD children characterized by greater severity, to better delineate abnormal gut function in autism and perhaps the entire pathophysiology of the disease in at least some individuals.

Keywords

Fermentation Tyrosine Toluene Polycyclic Aromatic Hydrocarbon Bacillus 

References

  1. Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011;11:22.PubMedCrossRefGoogle Scholar
  2. Alberti A, Pirrone P, Elia M, et al. Sulphation deficit in “low-functioning” autistic children: a pilot study. Biol Psychiatry. 1999;46:420–4.PubMedCrossRefGoogle Scholar
  3. Altieri L, Neri C, Sacco R, et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011;16:252–60.PubMedCrossRefGoogle Scholar
  4. Andersen A. Final report on the safety assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int J Toxicol. 2006;25:29–127.PubMedCrossRefGoogle Scholar
  5. Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.PubMedCrossRefGoogle Scholar
  6. Bal-Price AK, Coecke S, Costa L, et al. Conference report: advancing the science of developmental neurotoxicity testing (DNT) for better safety evaluation. ALTEX. 2012;29:202–15.PubMedGoogle Scholar
  7. Baron-Cohen S, Scott FJ, Allison C, et al. Prevalence of autism – spectrum conditions: UK school – based population study. Br J Psychiatry. 2009;194:500–9.PubMedCrossRefGoogle Scholar
  8. Bauman M, Kemper T. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23:183–7.PubMedCrossRefGoogle Scholar
  9. Beckh S, Pongs O. Members of the RCK potassium channel family are differentially expressed in the rat nervous system. EMBO J. 1990;9:777–82.PubMedGoogle Scholar
  10. Bergé-Lefranc D, Chaspoul F, Calaf R, et al. Binding of p-cresylsulfate and p-cresol to human serum albumin studied by microcalorimetry. J Phys Chem B. 2010;114:1661–5.PubMedCrossRefGoogle Scholar
  11. Birkett AM, Jones GP, Muir JG. Simple high-performance liquid chromatographic analysis of phenol and p-cresol in urine and feces. J Chromatogr B Biomed Appl. 1995;674:187–91.PubMedCrossRefGoogle Scholar
  12. Bone E, Tamm A, Hill M. The production of urinary phenols by gut bacteria and their possible role in the causation of large bowler cancer. Am J Clin Nutr. 1976;29:1448–54.PubMedGoogle Scholar
  13. Braunschweig D, Duncanson P, Boyce R, et al. Behavioral correlates of maternal antibody status among children with autism. J Autism Dev Disord. 2012;42:1435–45.PubMedCrossRefGoogle Scholar
  14. Buie T, Campbell DB, Fuchs 3rd GJ, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125:1–18.CrossRefGoogle Scholar
  15. Cafaro V, Notomista E, Capasso P, Di Donato A. Mutation of glutamic acid 103 of toluene o-xylene monooxygenase as a means to control the catabolic efficiency of a recombinant upper pathway for degradation of methylated aromatic compounds. Appl Environ Microbiol. 2005;71:4744–50.PubMedCrossRefGoogle Scholar
  16. Calderón-Guzmán D, Hernández-Islas JL, Espítia Vázquez IR, et al. Effect of toluene and cresols on Na+, K + -ATPase, and serotonin in rat brain. Regul Toxicol Pharmacol. 2005;41:1–5.PubMedCrossRefGoogle Scholar
  17. Cerini C, Dou L, Anfosso F, et al. P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb Haemost. 2004;92:140–50.PubMedGoogle Scholar
  18. Chang MC, Wang TM, Yeung SY, et al. Antiplatelet effect by p-cresol, a uremic and environmental toxicant, is related to inhibition of reactive oxygen species, ERK/p38 signaling and thromboxane A2 production. Atherosclerosis. 2011;219:559–65.PubMedCrossRefGoogle Scholar
  19. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13:171–81.PubMedCrossRefGoogle Scholar
  20. Chiu CA, Lu LF, Yu TH, et al. Increased levels of total P-Cresylsulphate and indoxyl sulphate are associated with coronary artery disease in patients with diabetic nephropathy. Rev Diabet Stud. 2010;7:275–84.PubMedCrossRefGoogle Scholar
  21. Clayton TA, Baker D, Lindon JC, et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci USA. 2009;106:14728–33.PubMedCrossRefGoogle Scholar
  22. Comi AM, Zimmerman AW, Frye VH, et al. Familial clustering of autoimmune disorders and evaluation of medical risk factors in Autism. J Child Neurol. 1999;14:388–94.PubMedCrossRefGoogle Scholar
  23. Cummings JH, Hill MJ, Bone ES, et al. The effect of meat protein and dietary fiber on colonic function and metabolism. II. Bacterial metabolites in feces and urine. Am J Clin Nutr. 1979;32:2094–101.PubMedGoogle Scholar
  24. D’Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85:1076–9.PubMedCrossRefGoogle Scholar
  25. Dawson LF, Donahue EH, Cartman ST, et al. The analysis of para-cresol production and tolerance in Clostridium difficile 027 and 012 strains. BMC Microbiol. 2011;11:86.PubMedCrossRefGoogle Scholar
  26. De Bruin A. Metabolism of occupational agents. In: Biochemical Toxicology of Environmental Agents. Amsterdam: Elsevier/North-Holland Biomedical Press; 1976. p. 87–170.Google Scholar
  27. De Magistris L, Familiari V, Pascotto A, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51:418–24.PubMedCrossRefGoogle Scholar
  28. De Smet R, Van Kaer J, Van Vlem B, et al. Toxicity of free p-cresol: a prospective and cross-sectional analysis. Clin Chem. 2003;49:470–8.PubMedCrossRefGoogle Scholar
  29. Dou L, Cerini C, Brunet P, et al. P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines. Kidney Int. 2002;62:1999–2009.PubMedCrossRefGoogle Scholar
  30. Dyck LE, Kazakoff CW, Dourish CT. The role of catecholamines, 5- hydroxytryptamine and m-tyramine in the behavioural effects of m-tyrosine in the rat. Eur J Pharmacol. 1982;84:139–49.PubMedCrossRefGoogle Scholar
  31. Ecker C, Marquand A, Mourão-Miranda J, et al. Describing the brain in autism in five dimensions – magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. J Neurosci. 2010;30:10612–23.PubMedCrossRefGoogle Scholar
  32. Elliott AA, Elliott JR. Voltage-dependent inhibition of RCK1 K + channels by phenol, p-cresol, and benzyl alcohol. Mol Pharmacol. 1997;51:475–83.PubMedGoogle Scholar
  33. Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976;107:283–8.PubMedCrossRefGoogle Scholar
  34. Enstrom AM, Lit L, Onore CE, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33.PubMedCrossRefGoogle Scholar
  35. Ey E, Leblond CS, Bourgeron T. Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 2011;4:5–16.PubMedCrossRefGoogle Scholar
  36. Fatemi SH, Aldinger KA, Ashwood P, et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012;11:777–807.PubMedCrossRefGoogle Scholar
  37. Faure V, Cerini C, Paul P, et al. The uremic solute p-cresol decreases leukocyte transendothelial migration in vitro. Int Immunol. 2006;18:1453–9.PubMedCrossRefGoogle Scholar
  38. Finegold SM, Molitoris D, Song Y, et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis. 2002;35:6–16.CrossRefGoogle Scholar
  39. Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16:444–53.PubMedCrossRefGoogle Scholar
  40. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–8.PubMedCrossRefGoogle Scholar
  41. Garbett K, Ebert PJ, Mitchell A, et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis. 2008;30:303–11.PubMedCrossRefGoogle Scholar
  42. Goines P, Van de Water J. The immune system’s role in the biology of autism. Curr Opin Neurol. 2010;23:111–17.PubMedCrossRefGoogle Scholar
  43. Goines P, Haapanen L, Boyce R, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25:514–23.PubMedCrossRefGoogle Scholar
  44. Goodhart PJ, DeWolf WE, Kruse LI. Mechanism-based inactivation of dopamine beta-hydroxylase by p-cresol and related alkylphenols. Biochemistry. 1987;26:2576–83.PubMedCrossRefGoogle Scholar
  45. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–102.PubMedCrossRefGoogle Scholar
  46. Holmes E, Li JV, Athanasiou T, et al. Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. Trends Microbiol. 2011;19:349–59.PubMedCrossRefGoogle Scholar
  47. Jyonouchi H, Geng L, Streck DL, et al. Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. J Neuroimmunol. 2011;238:73–80.PubMedCrossRefGoogle Scholar
  48. Kawakami K, Makino I, Asahara T, et al. Dietary galacto-oligosaccharides mixture can suppress serum phenol and p-cresol levels in rats fed tyrosine diet. J Nutr Sci Vitaminol (Tokyo). 2005;51:182–6.CrossRefGoogle Scholar
  49. Kawakami K, Kojima K, Makino I, et al. Fasting enhances p-cresol production in the rat intestinal tract. Exp Anim. 2007;56:301–7.PubMedCrossRefGoogle Scholar
  50. Kawakami K, Makino I, Kato I, et al. p-Cresol inhibits IL-12 production by murine macrophages stimulated with bacterial immunostimulant. Immunopharmacol Immunotoxicol. 2009;31:304–9.PubMedCrossRefGoogle Scholar
  51. Kitagawa A. Effects of cresols (O-, M-, and P-isomers) on the bioenergetic system in isolated rat liver mitochondria. Drug Chem Toxicol. 2001;24:39–47.PubMedCrossRefGoogle Scholar
  52. Liabeuf S, Barreto DV, Barreto FC, et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2010;25:1183–91.PubMedCrossRefGoogle Scholar
  53. Lin CH, Yang JY. Chemical burn with cresol intoxication and multiple organ failure. Burns. 1992;18:162–6.PubMedCrossRefGoogle Scholar
  54. Lin CJ, Chen HH, Pan CF, et al. p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease. J Clin Lab Anal. 2011;25:191–7.PubMedCrossRefGoogle Scholar
  55. Lintas C, Sacco R, Persico AM. Genome-wide expression studies in autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol Dis. 2012;45:57–68.PubMedCrossRefGoogle Scholar
  56. Mandel HG. Pathways of drug biotransformation: biochemical conjugations. In: LaDu BN, Mandel HG, Way EL, editors. Pathways of drug biotransformation. Baltimore: Williams and Wilkins; 1971. p. 149–86.Google Scholar
  57. McFarlane HG, Kusek GK, Yang M, et al. Autism-like behavioral phenotypes in BTBR T + tf/J mice. Genes Brain Behav. 2008;7:152–63.PubMedCrossRefGoogle Scholar
  58. Meert N, Schepers E, Glorieux G, et al. Novel method for simultaneous determination of p-cresylsulphate and p-cresylglucuronide: clinical data and pathophysiological implications. Nephrol Dial Transpl. 2012;27:2388–96.CrossRefGoogle Scholar
  59. Meijers BK, Bammens B, De Moor B, et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int. 2008;73:1174–80.PubMedCrossRefGoogle Scholar
  60. Meijers BK, Van Kerckhoven S, Verbeke K, et al. The uremic retention solute p-cresyl sulfate and markers of endothelial damage. Am J Kidney Dis. 2009;54:891–901.PubMedCrossRefGoogle Scholar
  61. Miller M, Strömland K, Ventura L, et al. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci. 2005;23:201–19.PubMedCrossRefGoogle Scholar
  62. Nakabayashi I, Nakamura M, Kawakami K, et al. Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study. Nephrol Dial Transplant. 2011;26:1094–8.PubMedCrossRefGoogle Scholar
  63. Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5.PubMedCrossRefGoogle Scholar
  64. O’Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43:585–9.PubMedCrossRefGoogle Scholar
  65. OECD. m-/p-Cresol category, screening information data set, initial assessment report. Paris: UNEP; 2003. www.chem.unep.ch/irptc/sids/oecdsids/m-p-cresols.pdf.
  66. Parracho HM, Bingham MO, Gibson GR, et al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005;54:987–91.PubMedCrossRefGoogle Scholar
  67. Persico AM. Autisms. In: Rakic P, Rubenstein J, editors. Comprehensive developmental neuroscience. San Diego: Elsevier; 2012.Google Scholar
  68. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–58.PubMedCrossRefGoogle Scholar
  69. Ramakrishna BS, Roberts-Thomson IC, Pannall PR, et al. Impaired sulphation of phenol by the colonic mucosa in quiescent and active ulcerative colitis. Gut. 1991;32:46–9.PubMedCrossRefGoogle Scholar
  70. Renwick AG, Thakrar A, Lawrie CA, et al. Microbial amino acid metabolites and bladder cancer: no evidence of promoting activity in man. Hum Toxicol. 1988;7:267–72.PubMedCrossRefGoogle Scholar
  71. Roberts MS, Anderson RA, Swarbrick J. Permeability of human epidermis to the phenolic compounds. J Pharm Pharmacol. 1977;29:677–89.PubMedCrossRefGoogle Scholar
  72. Robertson MA, Sigalet DL, Holst JJ, et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J Autism Dev Disord. 2008;38:1066–71.PubMedCrossRefGoogle Scholar
  73. Rutter M. Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr. 2005;94:2–15.PubMedCrossRefGoogle Scholar
  74. Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41.PubMedCrossRefGoogle Scholar
  75. Schepers E, Meert N, Glorieux G, et al. P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant. 2007;22:592–6.PubMedCrossRefGoogle Scholar
  76. Schopler E, Reichler RJ, Rochen Renner BR. The childhood autism rating scale for diagnostic screening and classification of autism. New York: Irvington; 1986.Google Scholar
  77. Seak CK, Lin CC, Seak CJ, et al. A case of black urine and dark skin – cresol poisoning. Clin Toxicol (Phila). 2010;48:959–60.CrossRefGoogle Scholar
  78. Selmer T, Andrei PI. p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol. Eur J Biochem. 2001;268:1363–72.PubMedCrossRefGoogle Scholar
  79. Shaw W. Increased urinary excretion of a 3-(3-hydroxy-phenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. In the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13:135–43.PubMedCrossRefGoogle Scholar
  80. Singh VK, Rivas WH. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci Lett. 2004;355:53–6.PubMedCrossRefGoogle Scholar
  81. Singh VK, Warren RP, Averett R, et al. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997;17:88–90.PubMedCrossRefGoogle Scholar
  82. Song Y, Liu C, Finegold SM. Real-time PCR quantitation of Clostridia in feces of autistic children. Appl Environ Microbiol. 2004;70:6459–65.PubMedCrossRefGoogle Scholar
  83. Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989;30:405–16.PubMedCrossRefGoogle Scholar
  84. Thompson DC, Perera K, London R. Studies on the mechanism of hepatotoxicity of 4-methylphenol (p-cresol): effects of deuterium labeling and ring substitution. Chem Biol Interact. 1996;101:1–11.PubMedCrossRefGoogle Scholar
  85. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002;1:352–8.PubMedCrossRefGoogle Scholar
  86. Tyler CV, Schramm SC, Karafa M, et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. 2011;116:371–80.PubMedCrossRefGoogle Scholar
  87. Vanholder R, De Smet R, Waterloos MA, et al. Mechanisms of uremic inhibition of phagocyte reactive species production: characterization of the role of p-cresol. Kidney Int. 1995;47:510–17.PubMedCrossRefGoogle Scholar
  88. Vanholder R, De Smet R, Lesaffer G. p-Cresol: a toxin revealing many neglected but relevant aspects of uraemic toxicity. Nephrol Dial Transplant. 1999;14:2813–15.PubMedCrossRefGoogle Scholar
  89. Vanholder R, Bammens B, de Loor H, et al. Warning: the unfortunate end of p-cresol as a uraemic toxin. Nephrol Dial Transplant. 2011;26:1464–7.PubMedCrossRefGoogle Scholar
  90. Veenstra-VanderWeele J, Blakely RD. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012;37:196–212.PubMedCrossRefGoogle Scholar
  91. Walsh P, Elsabbagh M, Bolton P, et al. In search of biomarkers for autism: scientific, social and ethical challenges. Nat Rev Neurosci. 2011;12:603–12.PubMedCrossRefGoogle Scholar
  92. Wang CP, Lu LF, Yu TH, et al. Serum levels of total p-cresylsulphate are associated with angiographic coronary atherosclerosis severity instable angina patients with early stage of renal failure. Atherosclerosis. 2010;211:579–83.PubMedCrossRefGoogle Scholar
  93. Wang L, Angley MT, Gerber JP, et al. A review of candidate urinary biomarkers for autism spectrum disorder. Biomarkers. 2011;16:537–52.PubMedCrossRefGoogle Scholar
  94. Wang CP, Lu LF, Yu TH, et al. Associations among chronic kidney disease, high total p-cresylsulfate and major adverse cardiac events. J Nephrol. 2013;26:111–18.PubMedCrossRefGoogle Scholar
  95. Whited GM, Gibson DT. Toluene-4-monoxygenase, a three component enzyme system that catalyzes the oxidation of toluene to p-cresol in Pseudomonas mendocina KR1. J Bacteriol. 1991;173:3017–20.PubMedGoogle Scholar
  96. Wilson ID. Drugs, bugs, and personalized medicine: pharmacometabonomics enters the ring. Proc Natl Acad Sci USA. 2009;106:14187–8.PubMedGoogle Scholar
  97. Wu ML, Tsai WJ, Yang CC, et al. Concentrated cresol intoxication. Vet Hum Toxicol. 1998;40:341–3.PubMedGoogle Scholar
  98. Yap IK, Angley M, Veselkov KA, et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010;9:2996–3004.PubMedCrossRefGoogle Scholar
  99. Yehuda S, Carasso RL, Mostofsky DI. Essential fatty acid preparation (SR-3) raises the seizure threshold in rats. Eur J Pharmacol. 1994;254:193–8.PubMedCrossRefGoogle Scholar
  100. Yokoyama MT, Carlson JR. Production of skatole and p-cresol by a ruminal Lactobacillus sp. Appl Environ Microbiol. 1981;41:71–6.PubMedGoogle Scholar
  101. Yokoyama MT, Tabori C, Miller ER, et al. The effects of antibiotics in the weanling pig diet on growth and the excretion of volatile phenolic and aromatic bacterial metabolites. Am J Clin Nutr. 1982;35:1417–24.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Unit of Child and Adolescent PsychiatryUniversity “Campus Bio-Medico”RomeItaly

Personalised recommendations